Multi-Omic analyses characterize the ceramide/sphingomyelin pathway as a therapeutic target in Alzheimer's disease.

Journal Article (Journal Article)

Dysregulation of sphingomyelin and ceramide metabolism have been implicated in Alzheimer's disease. Genome-wide and transcriptome-wide association studies have identified various genes and genetic variants in lipid metabolism that are associated with Alzheimer's disease. However, the molecular mechanisms of sphingomyelin and ceramide disruption remain to be determined. We focus on the sphingolipid pathway and carry out multi-omics analyses to identify central and peripheral metabolic changes in Alzheimer's patients, correlating them to imaging features. Our multi-omics approach is based on (a) 2114 human post-mortem brain transcriptomics to identify differentially expressed genes; (b) in silico metabolic flux analysis on context-specific metabolic networks identified differential reaction fluxes; (c) multimodal neuroimaging analysis on 1576 participants to associate genetic variants in sphingomyelin pathway with Alzheimer's disease pathogenesis; (d) plasma metabolomic and lipidomic analysis to identify associations of lipid species with dysregulation in Alzheimer's; and (e) metabolite genome-wide association studies to define receptors within the pathway as a potential drug target. We validate our hypothesis in amyloidogenic APP/PS1 mice and show prolonged exposure to fingolimod alleviated synaptic plasticity and cognitive impairment in mice. Our integrative multi-omics approach identifies potential targets in the sphingomyelin pathway and suggests modulators of S1P metabolism as possible candidates for Alzheimer's disease treatment.

Full Text

Duke Authors

Cited Authors

  • Baloni, P; Arnold, M; Buitrago, L; Nho, K; Moreno, H; Huynh, K; Brauner, B; Louie, G; Kueider-Paisley, A; Suhre, K; Saykin, AJ; Ekroos, K; Meikle, PJ; Hood, L; Price, ND; Alzheimer’s Disease Metabolomics Consortium, ; Doraiswamy, PM; Funk, CC; Hernández, AI; Kastenmüller, G; Baillie, R; Han, X; Kaddurah-Daouk, R

Published Date

  • October 8, 2022

Published In

Volume / Issue

  • 5 / 1

Start / End Page

  • 1074 -

PubMed ID

  • 36209301

Pubmed Central ID

  • PMC9547905

Electronic International Standard Serial Number (EISSN)

  • 2399-3642

Digital Object Identifier (DOI)

  • 10.1038/s42003-022-04011-6


  • eng

Conference Location

  • England